It is well known that hyaluronic acid (HA), a naturally-occurring glycosaminoglycan (GAG), plays a key role in wound healing. HA has a range of naturally occurring molecular sizes from 100 to 10,000,000 Da. HA is implicated in water homeostasis of tissues, in the regulation of permeability of other substances by steric exclusion phenomena and in the lubrication of joints. HA also binds specifically to proteins in extracellular matrix, on the cell surface, and within the cells cytosol, thereby having a role in cartilage matrix stabilization, cell motility, growth factor action, morphogenesis and embryonic development and inflammation. Unmodified HA has many important application in drug delivery and surgery. For example, it is used as an adjuvant for ophthalmic drug delivery. In addition, HA has important application in the fields of visco-surgery, visco-supplementation and wound healing. HA is also a building-block for biocompatible and biodegradables polymers with application in drug delivery, tissue engineering and visco-supplementation.
Hydrogels are formed by crosslinked polymers and are able to absorb high quantity of water without being dissolved. HA hydrogels are physically or covalently cross-linked HA gel. HA molecules are generally functionalized to allow reaction with a cross linker. Crosslinked HA hydrogels for example have been prepared by crosslinking with molecules such as di-epoxy-butane, ethylene-glycol di-glycidyl-ether (EGDGE) or poly-glycol diglycidyl-ether (PEGDE).
HA hydrogels have been used for several application including drug delivery applications. They are able to provide sustained, local delivery of a variety of therapeutic agent. Use of HA as a scaffold material in hydrogel has been pursued due to the biocompatibility, low toxicity, lack of immune response and biodegradability of HA hydrogel.
Although HA hydrogels have been studied for drug delivery applications, the delivery rates are difficult to control. If a hydrophilic drug is incorporated into the hydrogel, the incorporation is easy (large amounts can be loaded), but release is also rapid. On the other hand, it is difficult to get large amounts of hydrophobic drugs into such hydrogels, for solubility reasons. Any un-dissolved drug will migrate to the surface of the hydrogel and release in a burst (within a day or two).
There is therefore the need to provide further and improved drug/protein/nucleic acid sustain delivery formulations that allow an efficient and localized controlled release of hydrophobic and hydrophilic drugs, proteins or nucleic acid, avoiding the above mentioned drawbacks.